Table 4.

Histone mutations reported in pediatric high-grade gliomas.

Gene (Chromosome)	Histone Subtype	Mutation	Frequency	Tumor	Molecular, Biologic and Clinical Features
H3F3A (1)	H3.3	K27M	Up to 93%	DIPG and midline tumors	These mutations are restricted to midline gliomas (pons, thalamus, cerebellum, and spine). All K27M gliomas have a poor prognosis. Geneexpression profile of these tumors is similar to the expression profiles of tumors with a proneural/oligodendroglial phenotype. TP53 mutations and PDGFRA and TOP3A amplifications are frequent.
HIST1H3B (17)	H3.1	K27M	Up to 31%	DIPG	These mutations are highly specific for tumors localized in the pons (DIPG) and the gliomas displaying these mutations show better prognosis than those H3.3K27M-positive. Gene expression profile in these tumors is similar to the expression profiles in adult tumors with a mesenchymal/astrocytic phenotype. ACVR1 and BCOR gene mutations are frequent. Genomic alterations of chr1q and chr2 are frequent.
HIST1H3C (6)	H3.1	K27M	<3%	DIPG	Properties similar to HIST1H3B-mutated tumors.
HIST2H3C (6)	H3.2	K27M	<2%	DIPG	Properties similar to HIST1H3B-mutated tumors.
H3F3A (1)	H3.3	K27I	<1%	DIPG and midline tumors	Properties similar to H3.3K27M-mutated tumors.
H3F3A (1)	H3.3	G34R	12–14%	HGG	H3.3G34R/V tumors are almost entirely restricted to the cerebral hemispheres (16% in this location), particularly parietal and temporal lobes, are found predominantly in adolescent and young adults (median 15 years) and have a longer overall survival compared with other H3 mutant tumors. These tumors have a higher mutational burden than K27M gliomas. At the molecular level, frequent co-occurring events are TP53/ATRX alterations, PI3K and MAPK pathway mutations, MGMT promoter methylation. Genomic alterations of chr14q24 and chr17p13.1 are frequent.
H3F3A (1)	H3.3	G34L	<2%	HGG	Properties similar to G34R-mutated tumors.

DIPG: diffuse intrinsic pontine glioma; HGG: high-grade glioma.